Adenosine is an important mediator of numerous biological functions both in the nervous system and in peripheral tissues. It exerts its action by interacting with at least four different receptor (AR) subtypes (A1, A2a, A2b, and A3) (Fredholm, et al., J. International Union of Pharmacology. V. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 2001, 53, 527-552). Several studies on the action of adenosine in different tissues showed the potential benefits of ligands (agonists or antagonists) to AR for the treatment of several diseases. Thus, cardioprotective action has been attributed to A1AR,2 A2aAR3 and A3AR2b,4,5 agonists, whereas A1AR6 and A2aAR7 antagonists show potential anti-Alzheimer properties. A2aAR antagonists are actively studied as anti-Parkinson agents,8 and have also been found protective against quinolinic acid and free radical neuronal damage.9 A3 AR antagonists are under consideration for treatment of glaucoma.4,10 A selective A1AR agonist showed neuroprotective effect in a rat model of Huntington's disease.11 Finally, recent studies indicate that A3 AR maybe targets for cancer therapy and chemoprotection.12 
Such a range of possible therapeutic applications and the need of fully understand the pharmacological properties of each AR subtype prompted numerous efforts to discover more potent and selective ligands to each receptor subtype. Among many structural modifications reported in literature, L-nucleosides have been rarely considered, probably following early reports of little or no interactions of the L-entantiomers of adenosine, 2-chloroadenosine, 2-azidoadenosine, and N-ethylcarboxamidoadenosine (NECA) with A2 AR in different animal tissues.13 L-adenosine, a plant hormone, is also inactive on animal enzymes such as S-adenosyl-L-homocysteine hydrolase,14 and does not interact with mammalian nucleoside transporters.15 In the past, however, favorable features of L-nucleosides, such as low cellular toxicity16 and high metabolic stability,16,17 have been exploited in the design of successful antiviral and promising anticancer agents. The favorable features of L-nucleosides prompted us to evaluate L-3′-amino-3′-deoxy-N6-dimethyladenosine (L-PAN, 1) (FIG. 1), recently synthesized in our laboratory,18 as an AR agonist. At the same time, in order to evaluate the effect of the favorable 3′-amino and 5′-carboxamide substitutions, we prepared and evaluated the novel analog L-3′-amino-3′-deoxy-N6-methyladenosine-5′-N-methyluronamide (L-3′-AM-MECA, 2), enantiomer of compound 3, a simplified and A3AR-selective analog of the non-selective agonist IB-MECA (FIG. 1).